Fibronectin isoforms in skeletal development and associated disorders

Abstract

The extracellular matrix is an intricate and essential network of proteins and non-proteinaceous components that provide a conducive microenvironment for cells to regulate cell function, differentiation, and survival. Fibronectin is one key component in the extracellular matrix that participates in determining cell fate and function crucial for normal vertebrate development. Fibronectin undergoes time dependent expression patterns during stem cell differentiation, providing a unique stem cell niche. Mutations in fibronectin have been recently identified to cause a rare form of skeletal dysplasia with scoliosis and abnormal growth plates. Even though fibronectin has been extensively analyzed in developmental processes, the functional role and importance of this protein and its various isoforms in skeletal development remains less understood. This review attempts to provide a concise and critical overview of the role of fibronectin isoforms in cartilage and bone physiology and associated pathologies. This will facilitate a better understanding of the possible mechanisms through which fibronectin exerts its regulatory role on cellular differentiation during skeletal development. The review discusses the consequences of mutations in fibronectin leading to corner fracture type spondylometaphyseal dysplasia and presents a new outlook towards matrix-mediated molecular pathways in relation to therapeutic and clinical relevance.

Role of Fibronectin in Postnatal Skeletal Development

“…TGFβ is an essential growth factor for regulated chondrogenesis 45 , and TGFβ signaling regulates FN isoform levels during chondrogenesis and vice versa (refer to review 34 ). FN regulates TGFβ levels and its bioavailability via organizing LTBP1 assembly 46 .…”

Mutations in Fibronectin Dysregulate Chondrogenesis in Skeletal Dysplasia

“…Figure 3A-C). FN C123R and FN C231W chondrocytes showed significant dysregulation in several (5)(6)(7)(8)(9)(10)(11)(12) of the disulfide isomerase enzymes, which was more pronounced for the FN C123R mutant (Supp. Figure 3B,C).…”

“…In humans, FN is encoded by the 75kb fibronectin gene FN1 located on chromosome 2 (6), that gives rise to the ~8kb transcribed premature FN mRNA. This mRNA undergoes extensive alternative splicing of exons coding for three type III domains, the extra domains A and B (EDA and EDB) and the variable domain (V) to produce 27 known transcripts (7).The various FN isoforms are critical determinants of physiological and pathological processes associated with major organ systems, such as embryonic development, neuronal patterning, development and maintenance of lungs, mammary glands, blood vasculature, in fibrosis, cancer and others (8)(9)(10)(11). FN is secreted from cells as a 440kDa dimer linked via intramolecular disulfide bonds at the C-terminal end.…”

“…Mutations in FN were first reported in 2008, leading to glomerulopathy with fibronectin deposits (GFND) (OMIM #601894) [15]. We and others reported heterozygous autosomal dominant mutations in FN1 that cause a rare form of skeletal dysplasia termed "corner fracture" type spondylometaphyseal dysplasia (SMDCF) (OMIM #184255) [7,[16][17][18].…”

“…Mutations in FN were first reported in 2008 leading to glomerulopathy with fibronectin deposits (GFND)(OMIM #601894) (15). Following which we and others reported heterozygous autosomal dominant mutations in FN1 that cause a rare form of skeletal dysplasia termed as “corner fracture” type spondylometaphyseal dysplasia (SMDCF) (OMIM #184255) (7, 16–18). Affected SMDCF patients suffer from visible clinical implications such as short stature and overall growth defects, severe scoliosis, coxa vara, abnormal ossification of metaphyses, and presence of vertebral anomalies (16).…”